Protection Against Lethal Multidrug-Resistant Bacterial Infections Using Macrophage Cell Therapy

Abstract

Abstract. Multidrug-resistant (MDR) bacterial infections exert a tremendous burden on the public health system throughout the developing and developed world. Slowing development of novel antibiotic scaffolds, over-prescription of antibiotics, extensive agricultural antibiotic use, and the increasingly complex hospitalized patient populations undergoing treatment, all fuel the rise of highly MDR “superbugs.” Unfortunately, host-directed therapies to boost immune resistance to infection are not currently available for treatment of MDR pathogens. Hematopoietic cells are endowed with a variety of mechanisms to control microbial invasion. Macrophages in particular have long been appreciated as potent antimicrobial immune cells equipped with several receptors that allow for rapid recognition, phagocytosis, and killing of pathogenic microbes, coupled to secretion of immunostimulatory cytokines to further orchestrate a robust multifaceted antibacterial immune response. To investigate the utility of macrophages as a cell therapy for MDR bacterial infections, we developed a therapeutically translatable process to generate, harvest, and cryopreserve monocyte-derived macrophages (ICONIMAC™). These cells effectively killed both Gram-positive and Gram-negative MDR pathogens in vitro, and conferred protection in vivo against experimental lethal peritonitis and lung infection. Our discoveries provide a proof-of-concept for a novel immuno-therapeutic approach against MDR bacterial infections, urgently needed to supplement the diminishing antibiotic pipeline.